DESCRIPTION: (Applicant's Description) Ca2+ entry through voltage-gated Ca2+ channels in nerve terminals initiates the release of neurotransmitter at a synapse. Because small fluctuations in Ca2+ levels correlate with large changes in synaptic efficacy, regulation of Ca2+ influx through presynaptic Ca2+ channels can powerfully influence neurotransmision. Ca2+ currents through presynaptic P/Q type-channels undergo Ca2+-dependent facilitation that contributes to the short-term enhancement of synaptic transmission, but little is known about the underlying mechanism. The Ca2+-dependent properties of a number of ion channels are conferred directly by calmodulin, which also binds to the alpha1A-subunit of P/Q-type Ca2+ channels. Thus, the studies in this proposal will test the hypothesis that calmodulin binding to the alpha1A subunit mediates the feedback regulation of P/Q-type channels by Ca2+. Techniques in molecular biology and electrophysiology will be used to characterize the molecular determinants and functional impact of the calmodulin/Ca2+ channel interaction with respect to Ca2+-dependent facilitation of P/Q-type Ca2+ channels transfected in mammalian cells. The goal of the proposed studies is to elucidate how presynaptic Ca2+ channel modulation contributes to the fine-tuning of neurotransmission, which may be a first step in understanding the clinical manifestations of P/Q-type Ca2+ channel defects, such as epilepsy and migraine.